Bone tissue engineering scaffolds often require the use of osteoinductive growth factors (e.g. bone morphogenetic proteins, BMPs) to make them clinically viable. While promising, growth factors have significant drawbacks including their limited solubility, instability, immunogenicity, and high cost. Also, BMP-loaded scaffolds have been shown to induce most bone formation on the surface of the scaffold with limited cellular penetration into the bulk of the scaffold. To alleviate this problem, some researchers have delivered both BMPs and angioinductive growth factors (e.g. VEGF) to facilitate bone development throughout the scaffold. While constructs containing both types of growth factors have shown promise, the disadvantages of using growth factors still exist. Due to these limitations, there exists a need to develop novel strategies for bone regeneration therapies. Preliminary data from the PI's group provides evidence that hydrogen peroxide and calcium hydroxide can induce adipose-derived stem cells to produce their own VEGF and BMP- 2, respectively. Calcium peroxide, a FDA-approved food additive, dissociates into hydrogen peroxide and calcium ions in a gradual and controlled fashion. It is highly stable and inexpensive making it a clinically viable alternative to using growth factors. The objectives of th present research proposal are 1) to evaluate the angioinductive and osteoinductive potential of calcium peroxide in rabbit mesenchymal stem cells, 2) to compare these effects to the exogenous delivery of the growth factors VEGF and BMP-2, and 3) to create composite poly(lactide-co-glyoclide) / calcium peroxide sintered microsphere scaffolds and assess their capacity to facilitate bone regeneration. The biological performance of the scaffolds will be determined using a rabbit ulnar critical size defect model. We hypothesize the bioactivity of calcium peroxide will significantly improve bone tissue regeneration in vivo over growth factor loaded poly(lactide-co-glycolide) scaffolds. PUBLIC HEALTH RELEVANCE: The Laurencin laboratory has focused on developing tissue engineering strategies for the regeneration of orthopaedic tissues such as bone, cartilage, and ligament. To achieve these goals, we collaborate with experts from a wide range of scientific fields including clinicians, cell and molecular biologists, and engineers from the University of Connecticut and around the world. The innovation of the current proposal is the development of controlled release composite scaffolds that can induce angiogenesis and osteogenesis without the need for exogenous growth factors.